9-halo-4, 6-pregnadienes



United States Patent 3,105,832 9-HALO-4,6-PREGNADIENES Josef Fried, Princeton, NJ., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed June 9, 1961, Ser. No. 115,907 16 Claims. (Cl. 260-23955) This application is a continuation-in-part of my applications, Serial No. 489,769, filed February 21, 1955, and Serial No. 516,333, filed June 17, 1955, now U.S. Patent No. 3,000,915.

This invention relates to the synthesis of valuable steroids.

One object of this invention is the provision of an advantageous process of preparing steroids of .the 4,6-pregnadiene (including pregnatriene) series, having a 9a-halo group and an llp-hydroxy or ll-keto group. Another object of this invention is the provision of steroids of the 4,6-pregnadiene (including pre'gnatriene) series, having a 9a-halo group and an 11 B-hydroxy or 11-keto group, which compounds are useful either for their own physiological action or as intermediates in the preparation of physioligically-acti-ve derivatives.

The preferred 9a-halo compounds of this invention are those which are comprehended by the general formula:

wherein R is hydrogen, R' is hydroxy or together R and R' is a keto or ketazlized keto group (preferably the free keto group), R" is hydrogen, R is B-hydroxy, or together R" and R' is a keto group, X is an a-halogen group, Z is hydrogen or a-hydroxy, and Y is hydrogen, hydroxy or acyloxy (preferably the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms). Sui-table acyloxy radicals are those formed with lower alkanoic acids, such as acetic, propionic, heptanoic and caprylic acid; monocyclic aryl carboxylic acids, such as benzoic and toluic acid; monocyclic aryl lower alkanoic acids, such as phenacetic and fi-phenylpropionic acid; lower alkenoic acids; cycloalkane carboxylic acids; and cycloalkene carboxylic acids.

The steroids of this invention, which are unsaturated in the 4,5 and 6,7 positions and have a 9u-halo group and an 11 ,B-hyd-roxy or ll-keto group, are physiologicallyactive compounds which possess glucocorticoid as well as mineralocorticoid activity. Thus, the new steroids of this invention can be administered instead of, and in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, or in the same manner as desoxycorticosterone in the treatment of Addisons disease or adrenal insufliciencies. The dosage for such administration is of course dependent on the $105,832 Patented Oct. 1, 1963 '170t-dlO1-3,20-dl0116 and 9u-chloro-A -pregnadiene-11,8,

17lX-di01-3,20-di0l16) the 9ot-hailo-A -pregnadiene-17aol-3,11,20-triones- (e.g., 9u-fiuoro-A -pregnadiene-17aol-3,11,20-trione and 9a-chloro-A -pregnadiene-17e-ol- 3,11,20-trione), the 9a-halo-A -pregnadiene-11 3,21-diol- 3,20-diones (e.g., 9a-fluOrO-N' -pregnadiene-11/3,21*cliol- 3,20-dione and 9a-chloro-A -pregnadiene-11 8,21-diol- 3,20-dione) and the 21-esters thereof (e.g., the 21-1ower alleanoates such as the ZI-acetate and 2l-propionate), the 9a-halo-A -pregnadiene-21-ol-3,11,2O-triones (e.g., tfluoro-A -pregnadiene-21-ol-3,11,2O-t1ione and 9a-chloro- A -pregnadiene-21-ol-3,11-20-trione) and the 21-esters thereof, the 9a-halo-A -pregnadiene-11B,17a-21-t1iol-3, 20-diones (i.e., 9a-fluoro-A -pregnadiene-11B,17a,21-trio1 3,20 dione, 90c chloro A pregnadiene 11,6, 17cc 21 triol 3,20 dione, 90c bromo A pregnadiene-1 lfi,17oc-21-t1iO1-3,20-di011, and 9a-iodo-A -pregnadiene-l1,8,17a,21-triol-3,20-dione) and the ZI-e-sters thereof (e.g., 2l-lower-alkanoyl esters), and the 9a-halo- A pregnadiene 17a 21 diol 3,11,20 triones (e.g., 90 fluoro A pregnadiene c,21 diol 3,11,20- trione and 9a-chloro-A -pregnadiene-17a,21-diol-3,11,20- trione) and the 21-esters thereof (e.g., 21-lower alkanoyl esters).

The steroids of this invention can be prepared by a number of ditferent processes. A particularly advantageous process for forming the steroids of this invention consists in using one of the 9e-hatlo-11/3-hydroxy or ll-keto steroids disclosed in U.S. Patent No. 2,852,511 as a starting material. Representative of these steroids are the 9ot-halo-1lfi-hydroxyprogesterones, the 9a-haloll-ketoprogesterones, the 9a-halo-1lfl,17e-dihydroxyprogesterones, the 9a-halo-17a-hydroXy-11-ketoprogesterones, the 21-esters of 9a-halocorticosterone (e.g., the 21-1ower alkanoyl esters, such as the ZI-acetate), the 21-ester of 9a-halo-11-dehydrocorticosterone, the 21-esters of 9a-halohydrocortisone, and the 9oc-halOCOItiSOI16S, wherein the halogen has an atomic number no higher than 35, preferably no higher than 17. One of these representative steroids is hydrogenated to saturate the 4,5 double bond to form the corresponding allopregnane derivative. This step in the process may be carried out by means of hydrogen in the presence of a palladium catalyst with or without a carrier, such as barium sulfate, charcoal, calcium carbonate, etc. Other known hydrogenation procedures can, of course, be used instead. If A 9a-halo-11fi-hydroxy or ll-keto allopregnane is used initially, the first step in the process can, of course, be dispensed with the allopregnene can be used directly in the next step of the process.

The allopregnane containing a 9ot-halo group, wherein the halogen has an atomic number no higher than 35 3 (preferably no higher than 17) and an llfi-hydroxy or ll-keto group is then treated with two moles of bromine per mole of steroid in a suitable organic solvent such as an acid (e.g., a lower alkanoic acid, such as acetic acid) to yield a 2,4-dibromo derivative as the major product, the preferred compounds being those of the general formula I Br wherein Y is hydrogen or acyloxy (e.g., a lower alkanoyloxy, such as acetoxy), and R, R, R", R', and X and Z are as hereinbefore defined.

The brominated allopregnanes are then dehydrobrominated to yield a mixture of 1,4-pregnadiene and 4,6- pregnadiene derivatives, which may be separated by chromatography, as more fully detailed in the examples following. The dehydrobromination may be done, inter alia, by heating the steroid in the presence of an organic base, such as a lower alkylated pyridine (e.g., collidine), with or without a lithium halide salt, or by treating the steroid with a lithium halide (e.g., lithium chloride) in an organic solvent, such as a lower fatty acid amide (e.g., dimethyl formamide) to form the unsaturated derivative.

The 9a-halo11;8-hydroxy steroids formed by the prefer-red process of this invention can then either be oxidized with chrornic oxide in the known manner to produce the corresponding Qa-halo-II-keto derivatives, or they can be reacted with a dehydnohalogenating agent, when the halogen atom is bromine or chlorine, to form the 9B,11B-oxido derivative, as more fully disclosed hereinafter. Furthermore, if a ZI-acyloxy steroid is used as the reactant in the above steps, the esterifying group in the Ill-position can be hydrolyzed by treating the steroid with an alkali metal salt of carbonic acid (e.g., potassium bicarbonate or potassium carbonate) for example, in an organic solvent such as an alcohol (e.-g., methanol) to form the free 21-011.

Those steroids of this invention which contain a 21- hydroxyl group are also useful as intermediates in the preparation of corresponding steroid derivatives unsubstituted in the 2l-position. This conversion is effected by converting the 21-hydroxy steroid, having a Qa-flUOIO (or chloro) and an 11 fl-hYzdlOXY (or ll-keto) substituent, into the corresponding 21-alkanesulfonyloxy derivative thereof and converting the latter into the corresponding 21-unsu bstituted derivative, either directly or through the 21-iodide derivative.

The preferred compounds preparable by this process are those which are comprehended by the general formula E C=O RI! i Z BK? /5\/ x a l wherein R, R, R, R' and Z are as hereinbefore defined and X is ot-fillOIO or a-chloro.

Representative steroids preparable by this process of products of this invention are obtained directly.

4 the invention include: 9a-fluoro-A -pregnadiene-l1,8, 17oz diol 3,20 dione; 9a chloro A pregnadiene- 115,170: diol 3,20 dione; 9oz fiuoro A pregnadiene 1702 01 3,11,20 -t1ione; 9oz chloro A pregnadicne l7a-ol-3,11,20 trione; 9s fiuoro A preg nadiene 11 fi,ol 3,20 dione; 9oz chloro A preg-v nadiene 11 {3 ol 3,20 dione; 9a fluoro A pregnadiene-3 ,1 1,20-trione; and 9a-chloro-A -pregnadiene- 3,11,2'0-trione.

To prepare these 9a-halo compounds, a steroid of the general formula i wherein R, R, R", R, X and Z are as hereinbefore. defined, is reacted with an alkanesulfonyl halide, alkanesulfonyl chlorides being preferred, but other halides such as bromides and iodides beirrg utilizabzle. Although any alkanesulfonyl chloride may be used, the alkane group is preferably a lower alkane, methanesulfonyl chloride CHaOSOaB/ wherein R'"' -is alkyl (preferably lower alkyl) and R, R, R", R", X and Z are as hereinbefore defined.

The 2l-alkanesulfonyloxy intermediates are then reacted With a metal iodide (such as an alkali metal iodide, and particularly sodium iodide) in an organic solvent. The reaction is preferably conducted at an elevated temperature (e.g., at reflux). The nature of the product will depend on the organic solvent selected. If an. acidic solvent, such as a lower alkanoic acid (particularly glacial acetic acid) is chosen, the 21-unsubstituted final If, however, a neutral solvent such as an alcohol or a ketone (particularly acetone) is selected, then a 21-iodated intermediate is produced. Such 21-iodo intermediate can then be converted to its ZI-unsubstituted derivative, either'in situ or in a second step, by reacting (preferably heating) the former with an alkali metal iodide in an acidic solvent or with a metal bisulfite (such as an alkali metal bisulfite,

particularly sodium bisulfite) in an inert solvent, such as an acidic solvent to prepare the final products of this invention.

For the purpose of illustrating the processes of this invention, reference is made to the following schematic 3,105,832 5 6 analysis employing the ZI-acetate esters of 9a-ha10hydrocortisone and 90c-hZ11OCOXtiSODfl as starting materials:

The following examples are illustrative of the invention (all temperatures being in centigrade) EXAMPLE 1 9oz-Flu0r0-A -Pregnadiene-1 118,1 7a,.21 -Trz'ol-3,20-D ione 21-Acetate (XVII) (a) PREPARATION OF 9a.FLUOROALLOPREGNANE-l1B, l7u, 21-TRIOL-3,20-DIONE Zl-ACE'IATE (V) A'solution of 2.5 grams of 9ot-fiuorohydrocortisone acetate in 75 ml. of 95% alcohol is agitated in an atmosphere of hydrogen at room temperature and ordinary pressure in the presence of 500 mg. of 5% palladium on barium sulfate catalyst. After the absorption of 160.5 m1. of hydrogen, the reduction comes to a standstill. The catalyst is filtered off and the 9ufluoroallopregnane- 1lB,17a,2l-triol-3,20-dione ZI-acetate crystallized by successive concentrations of the filtrate. A total of about 2.17 grams of material approximately (87% of theory) is obtained, having the following properties: M.P., about 236-237"; [u] +66 (c., 0.96 in acetone);

w 2.82 2.97;. (OH), 5.75, (21-acetyl), 5.81,. 21-

keto) 5.97,. (3-keto); was 293,. 6:110

Anal.Calcd. for C H O F (424.49): C, 65.54; H, 7.87. Found: C, 65.34; H, 7.69.

Essentially the same result is obtained when the hydrogenation is conducted in ethyl acetate. 9a-fiuoroallopregnane 11B,l7a,2l-triol-3,20-dione 21-acetate crystallizes with ethyl acetate of crystallization, and it is desirable in this case to recrystallize from alcohol in order to obtain it free of the ethyl acetate. Other 2l-esters at 9a-fiuorohydrocortisone such as the propionate valerate, or caprylate, can, of course, be substituted for the 21- acetate in Example 1.

Similarly, if 9a-ChlOIOhYdIOCOltiSOHC acetate (II), 9afluorocortisone acetate (III), or 9a-chlorocortisone acetate (IV) is substituted for 9a-fiuorohydrocortisone acetate in the procedure of Example 1., 9ot-chloroallopregnane-l1B,17a,21-triol-3,20-dione 21-acetate (VI), 90:- fluoroallopregnane-l7a,2l-diol-3,l1,20-trione 21 acetate (VII), and 9a-chloroallopregnane-l7a,2l-diol-3,11,20- trione 2l-acetate (VIII) are formed, respectively.

(b) PREPARATION OF 9a-FLUOR0-A -PREGNADIENE 11fl,17a,21-TRIOL-3,ZO-DIONE zl-ac'm'ra'ma To a solution of 2.120 grams of 9u-fluoroallopregnanel1{3,17a,21-triol-3,20-dione 21-acetate in 100 ml. of glacial acetic acid is added 0.05 ml. of 1.3 N hydrobromic acid in acetic acid, and then dropwise with stirring a solution of 1.52 g. of bromine in 19 ml. of acetic acid. After standing at room temperature for one hour, 1.1 g. of potassium acetate is added, and the mixture concentrated in vacuo to small volume. After the addition of water, the suspension is extracted with chloroform and the chloroform solution washed with water, sodium bicarbonate solution and again with water. Removal of the solvent in vacuo leaves the crude 2,4-dibromo-9wfluoroallopregnane-l1f3,l7a,2l-triol-3,20-dione 21-acetate (IX) as an amorphous residue, which is debrominated with collidine without further purification. For this purpose it is dissolved in 25 ml. of collidine and refluxed for 30 minutes in an atmosphere of nitrogen. The mixture is diluted with chloroform and the collidine removed by extraction with dilute sulfuric acid. After washing with sodium bicarbonate solution and water, the chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in 16 ml. of chloroform and the resulting solution diluted with 48 ml. of benzene. The mixture is centrifuged and chromatographed on 30 g. of sulfuric acid-washed alumina. Elution of the column with 1 part of chloroform and 3 parts of benzene produces a mixture of by-products, which is followed by 91x fluoro- A pregnadiene 11B,17u,2l-triol-3,20-dione Zl-acetate (XVII) when the eluting fluid is changed to a mixture of equal parts of chloroform and benzene. Recrystallization of the combined fractions from ethyl acetate affords the pure substance having the following properties: M.P. about 209- 211; 3 +l39 (c., 0.76 in CHCl (acetyl), 5.80 (ZO-keto), 6.07 1,, 6.12pm, 6.20 (N -3- ketone) acetone-hexane has the following properties: M.P. about 24l244; +99 (c., 0.34 in acetone);

N23; 238 m (6: 14,700) $32 2.93 3.02 1 (OH), 5376 (acetyl), 5.85; (20-keto), 6.02 6.19 6.26;; (A -3- keto).

Aualysis.-Calcd. for C H O F (420.46): C, 65.70; I

H, 6.95. Found: C, 65.88; H, 7.20.

9oz fiuoro A pregnadiene l1fl,l7a,21 .triol- 3,20-dione 2l-acetate possesses about 30 times the activity of cortisone acetate in the rat liver glycogen assay.

9a fiuoro A pregnadiene l1fi3,17a,21 triol- 3,20-dione 21-acetate and its A -isomer can alsobe produced by the procedure of the following example:

EXAMPLE 2 A solution of 600 mg. of 2,4-dibromo-9a-fluoroallopregnane-l1,5,l7a,21-triol-3,20-dione 2l-acetate (IX) and 255 mg. of lithium chloride in 5 ml. of dimethylforman'k' ide is heated on the steam cone for 2 hours in an atmosphere of nitrogen. The mixture is diluted with water and the resulting suspension extracted with chloroform. The chloroform solution is washed with water, sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue, on chromatography as described in Example l(b furnishes the desired substances in pure form.

Similarly, if 9u-chloroallopregnane-l1B,17a,21-triol- 3,20-dione 21-acetate (VI), 9u-fiuoroallopregnane-170:,21- diol-3,l1,20-trione 2l-acetate (VII), or 9ct-chloroallopregnane-l7a-2l-diol-3,l1,20-trione 21-acetate (VIII) is substituted for 9a-fluoroallopregnane-11,8,17og21-triol- 3,20-dione 2l-acetate in the process of Example 1(b), the intermediates 2,4-dibromo-9a-chloroallopregnane- 115,l7zx,2l-triol-3,20-dione 2l-acetate (X), 2,4-dibromo- 2l-ace- 9e-fiuoroallopregnane- 1 7a,2 1-diol-3,1 1,20-trione tate (XI), and 2,4 dibromo 9a chloroallopregnane- 17,2l-diol-3,11,20-trione ZI-acetate (XII) are obtained, respectively. These dibrominated intermediates can then be converted to a mixture of their respective A -pregnadienes (XIV to XVI) and A -pregnadienes (XVIII to XX) by the procedures of Examples 1(b) and 2. The mixture is then separated chromatographically by the method disclosed in Example 1(b).

Furthermore, if another 9a-halo steroid of the pregnane series is substituted for the 9a-halohydrocortisones (acetate) and 9a-halocortisones (acetate) employed as described hereinbefore, the corresponding A and A derivatives are obtained. Thus, Qua-fluorocorticosterone acetate yields 9m-fiuoro-A -pregnadiene-ll,8,2l-diol-3,20-

dione 2l-acetate and 9a-fluoro-M -pregnadiene-116,21- diol-3,20-dione 2l-acetate; z-chlorocorticosterone acetate yields 9a-chloro-A -pregnadiene-115,21-diol-3,20-dione 21-acetate and 9wchloro-h -pregnadiene-115,2l-diol- 3,20-dione 2l-acetate; 9a-luoro-ll-dehydrocorticosterone acetate yields 9ot-fiuoro-A -pregnadiene-21-ol-3,l1,20-

trione 21-..cetate and 9oc- .uoro-A -pregnadiene-2l-ol- 3,11,20 trione 21 acetate; 90'. 4 chloro-l l-dehydrocorticosterone acetate yields 9a-chloro-A -pregnadiene-21-ol- 3,11,20-trione 21-acetate and 9or-chloro-A -pregnadiene- 21-ol-3,11,20-trione 21-acetate; 9a-fiuoro-11;3,17a-dihydroxyprogesterone yields 9a fluoro A pregnadiene- 11B,17a-diol-3,20-dione and 9a-fluoro-A -pregnadienel1B,17a-diol-3,20-dione; 9a-fluoro-11;S-hydroxyprogesterone yields 9a-fluoro-A -pregnadiene-11;8,ol-3,20-dione and 9a fiuoro 13 pregnadiene-l1fi-ol-3,20-dione; 9ozchloro-llfi-hydroxyprogesterone yields 9a-chloro-A pregnadiene-l1/3-ol-3,20-dione and 9ot-chloro-A -pregnadiene-l1;3,ol-3,20-dione; and 9a-fluoro-1l-ketoprogesterone yields 9a-fiuoro-A -pregnadiene-3,11,20-trione and 9a-fiuoro-A -pregnadiene-3 ,1 1,20-trione.

The 21-esterifying group may be hydrolyzed by treating the steroid with an alkali metal salt of a weak acid (e.g. potassium carbonate or potassium bicarbonate) in an organic solvent (e.g. methanol) to yield the free 21-01. By this method the 9u-halo-M -pregnadiene-11B,17a,21- triol-3,20-dione-(or 17c,21-diol-3,11,20-trione) 21-acetates are converted to the free 21-ols.

If an llfi-hydroxy steroid is used as the starting material, the resulting llfi-hydroxy products may be oxidized to the corresponding ll-keto derivatives by treating the products with an oxidizing agent such as chromic oxide.

EXAMPLE 3 9a-Fluoro-A -Pregnadiene-1 15,1 7a,21-Tri0l- 3,20-Dine (XXI) To a solution of 250 mg. of 6,7-dehydro-9a-fluorohyrocortisone acetate (XVII) in 7.5 ml. of methanol is added under nitrogen a solution of 1.2 ml. of a 10% aqueous potassium carbonate solution, which has been boiled for 1 minute and cooled under nitrogen. After 25 minutes at room temperature 0.25 ml. of glacial acetic acid is added to the mixture and the methanol removed in vacuo. The residue is taken up in ethyl acetate, washed with water and the ethyl acetate solution dried over sodium sulfate. Evaporation of the solvent leaves a crys talline residue consisting essentially of 6,7-dehydro-9afiuorohydrocortisone (XXI). After recrystallization from 95% ethanol the substance has the following properties: M.P. about 257259 (dec.); +101 (0., 0.45 in 95% ethanol);

A316,; 281 m (e=25,600); A252 2.95;; (OH), 5.85;; (20- keto), 6.10 6.19;, 6.31;; (A -3-ketone) Analysis.-Calcd. for C I-1 0 5 (378.43): C, 66.65; H, 7.19. Found: C, 66.30; H, 7.00.

In a similar manner, by substituting the 21-acetoxy derivatives of 9ot-chloro-A -pregnadiene-11,8,17wdi0l-3, 20 dione (XVIII), 9a-luoro-n -pregnadiene-17u-ol-3, 11,20-trione (XIX) and 9wchloro-A -pregnadiene-17aol-3,11,20-trione (XX) for the 6,7-dehydro-9a-iluorohydrocoitisone acetate in Example 3, 9a-chloro-A -pregnadione-115,17u,21-triol3,20-dione (XXII), 9a-fiuoro-A pregnadiene-17ct,21-diol-3,11,20-trione (XXIII) and 90:.- chloro A pregnadiene 1711,21 diol 3,11,20 trione (XXIV) are prepared respectively.

EXAMPLE 4 (a) PREPARATION OF 9aFLUORO-A -PREGNADIENE- 11B,l7a,21-TRIOL-3,20-DIONE 21-MESYLATE (XXV) To a solution of 175 mg. 6,7-dehydro-9a-fluorohydrocortisone (XXI) in 4 ml. of dry pyridine is added at 0 a solution of 0.1 ml. of methanesulfonyl chloride in 1 ml. of chloroform. After 2% hours at 0 ice water is added and the mixture extracted with chloroform. Extraction of the chloroform solution with dilute sulfuric acid, water, sodium bicarbonate solution and water followed by evaporation of the chloroform in vacuo fur- 16 nishes a residue consisting of essentially pure 6,7-dehy dro-9a-fluorohydrocortisone 21-mesylate (XXV). Recrystallization from ethanol yields the pure mesylate having the following properties: M.P. about 237238 (dec.); +94 (c., 0.21 in 95% alcohol);

hilt- 281 m (e=27,500); Ami? 2.85,u, 2.98;. (OH), 5.76;. (ZO-keto), 6.05 6.1O;1., 6.18, 6.30;; (At' -3-ketone) Analysis.-Calcd. for C H O FS (456.51): C, 57.78; H. 6.40; S, 7.02. Found: C, 58.19; H, 6.05; S, 7.54.

In a similar manner, by substituting 9a-chloro-A pregnadiene-l 1B,17u,21t1i01 3,20 dione, 9u-fluoro-A pregnadiene-17oz,21-diol-3,11,20-trione and 9achloro-A pregnadiene-17a,21-diol-3,11,20-trione for the 9oz-fll10l0- n -pregnadiene-l113,17a,21-triol-3,20- dione, the corresponding 2l-mesylates (XXVI to XXVIII) are prepared.

Furthermore, the procedure of Example 4(a) is operative in the conversion of all 9a-fiuoro (or chloro)-21- hydroxy-M -pregnadienes to the corresponding 21-mesylate derivatives.

(b) PREPARATION OF 9aFLUORO-2'1-IODO-A '-PREGNA- DIENE-l1fi,l7a.-DIOL-3,20-DIONE (XXIX) A solution of 190 mg. of 6,7-dehydro-9a-fiuorohydrocortisone 21-mesylate (XXV) and 723 mg. of sodium iodide in 7.2 ml. of acetone is refluxed for 10 minutes. The reaction mixture is diluted with water until all the sodium mesylate has dissolved. The solution is allowed to cool slowly. After concentration in vacuo the crystals are filtered and recrystallized from ethanol. Pure 90:- fluoro-21-iodo-A -pregnadiene-116,170; diol-3,20-dione (XXIX) has the following properties: M.P. about 225 (dec.); (c., 0.33 in absolute alcohol);

max.

(A -3-ketone) Analysis.Calcd. for C H O FI (488.34): C, 51.65; H, 5.37; I, 25.99. Found: C, 51.93; H, 5.68; I, 26.58.

In a similar manner, by substituting the 21-mesyloxy derivatives of 9a-chloro-n -pregnadiene-11;8,17a-diol-3, 20 dione (XXVI), 9a fiuoro-n -pregnadiene-17ot-ol-3, 11,20-trione (XXVII) and 9a-chloro-A -pregnadiene- 17a-ol-3,11,20-trione (XXVIII) for the 9a-fluoroA pregnadiene-l1B,17a,21-triol-3,20 dione 21 mesylate of Example 4(b), the corresponding 21 -iodo derivatives (XXX to XXXII) are produced.

(0) PREPARATION OF 9a-FLUORO-A -PREGNADIENE- 11B,17a-DIOL3,20-DIONE (XXXIII) To a solution of mg. of S u-fiuoro-21-iod0-A pregnadiene-l1,8,17u-dio1-3,20-dione (XXIX) in. 1.4 ml. of pure dioxane is added 1.4 ml. of 5% aqueous sodium bisulfite solution. The mixture is heated on the steam bath for /2 hour and during this process crystals appear throughout the solution. After the addition of Water, the mixture is cooled and the crystals of 9a-fluoro-A -pregnadiene-l1fi,17o-diol-3,20-dione (XXXIII) are filtered off and washed with water. Recrystallization of the crude crystals (about 92 mg.) from 95% ethanol furnishes the pure compound having the following properties: M.P. about 294-296" (dec.); +112 (c., 0.33 in dioxane);

is, 281 mp (e=26,000); 3 2.99 (OH), 5.87;; (20- keto), 6.10;, 6.18 6.30;; (A -3-ketone) Analysis.-Calcd. for C H O F (362.43): C, 69.59; H, 7.51. Found: C, 69.66; H, 7.48.

In the same manner as Example 4(c), the 21-iodo derivatives of 9u-Ch1010 A pregnadiene-l1,8,17u-dio1- 3,20-dione (XXX), 9cc-flll0l'0 A -pregnadiene-17a-ol- 3,11,20-trione (XXXI) and 9ot-chloro-n -pregnadienec-O1-3,11,20- l1'i0116 (XXXII) are converted to their respective ZI-unsubstituted derivatives (XXXIV t0 XXXVI).

Furthermore, the procedures of Example 4 are also operative in the conversion of 9oc-fill0IO (or chlor0)-A 7 l l pregnadiene-l1,8,21-diol-3,20-dione and 9a-fiuoro (or chloro) -A -pregnadiene-21-ol-3,11,20-trione to their corresponding ZI-unsubstituted derivatives.

The 9a-bromo and 9a-iodo-A -pregnadiene steroids of this invention are preferably prepared indirectly from the corresponding 9a-chloro-1113-hydnoxy-A pregnadiene derivatives by way of the 9 8,11 fi-oxido intermediates of this invention, the preferred 913,11fi-oxido intermediates being those of the general formula wherein R, R, Z and Y are as hereinbefore defined. Thus the 9u-chloro-11fi-hydroxy steroid is reacted with a salt of a strong base and a weak acid, such as an alkali metal carbonate (e.g., potassium carbonate) or an alkali metal alkoxide (e.g., sodium methoxide), and the corresponding 93,11/3-oxido compound thus formed is then reacted with a hydrogen halide (e.g., hydrobromic acid and hydro iodic acid) to form the corresponding 9a-halo-11B-hydroxy derivative. The series of steps can be represented by the following schematic analysis and examples:

(EHsOOCCH C=O HOW Y's It should be noted that it the 9ot-chloro steroid has an esterified hydroxy group in the 2l-position, this group is hydrolyzed, and a free 21-01 is produced. The ZI-hydroxy group can, however, later be esterified by treatment with the desired acyl halide or acid anhydride to form either a tive.

EXAMPLE 5 9B,]1[3-Oxido-M -Pregnadiene-1 704,21 -Di0l-3,20- Dione (XXXVII) To a solution of 100 mg. of 9a-chloro-u -pregnadiene- 11B,17e-2l-triol-3,20-dione 21-acetate (XVIII) in ml. of methanol is added a solution of 100 mg. of potassium carbonate in 0.5 ml. or oxygen-free water. Nitrogen is passed through the resulting solution for 5 minutes, and the mixture is allowed to remain at room temperature for three hours. Acetic acid is added to neutralize the carbonate, and after the addition of 5 ml. water, the methanol is removed in vacuo. The remaining aqueous sus- 4 pension is extracted with chloroform, the chloroform exsea tract washed with water and dried over sodium sulfate. Evaporation of the solvent leaves a residue of the desired 9,8,l1fi-epoxide (XXICVH).

In a similar manner, by using 9a-chloro-Ah -preg'nadiene 11B,Z1-diol-3,20-dione ZI-acetate and 9a-chloro-A pregnadiene-l1,8-ol-3,20-dione as a starting material, 9,8,

11B-oxido-A: -pregnadiene-2l-ol-3,20-dione and 95,11,6- V oxido-A -pregnadiene-3,ZG-dione are formed, respectively,

EXAMPLE 6 9a-Brom0-A -Pregnadiene-l 1[i,17a,21-Triol-3,20- Dione (XXXVHI) To a solution of 25 mg. of 93,1lfl-oxido-M- -pregnadiene-17 x,21-diol-3,20-dione (XXXVII) in 1 of chloroform is added with shaking at room temperature 0.04 ml. 30% hydrobrornic acid in glacial acetic acid.

After 10 minutes, 10 ml. of chloroform is added, and.

the mixture is extracted with dilute sodium bicarbonate and with water. The chloroform solution is dried over sodium sulfate, and evaporated to dryness in vacuo; and the residue, 9oa-bromo-A -pregnadiene-11,9,1'7a,21:trio1 3,20-dione, is crystallized from acetone.

In a similar manner, by substituting 60% aqueous hydroiodic acid for hydrobromic acid in Example 6, the

corresponding QOC-iOdO compound (XXXIX) is formed.

Similarly, all other 95,11/8-oxido steroids of this invention can be converted to the corresponding 9a-bromo and 9oc-i0d0 derivatives by the method of Example 6. Furthermore, the 9zx-bromo and 9a-iodo, 11 fi-hydroxy derivatives obtained can be oxidized to the corresponding 9a-b1'0m0 or 9a-iodo ll-keto derivatives by reaction with chromic acid.

Another utilizable process for preparing the steroids of this invention comprises brominating an lla-hydroxy steroid of the allopregnane series (after hydrogenating the steroid, if there is unsaturation in the 4,5-position, as for example by means of hydrogen in the presence of a palladium catalyst with or without a carrier such as barium sulfate, and separating the allopregnane isomer from the coproduced pregnane derivative) to form a 2,4- dibromo derivative. Suitable starting steroids for this process include llwhydroxyprogesterone, lla,l7ot-dihydroxyproges-terone, the 21-esters (e.g. 21-acetate) of epicorticosterone, and the 21-esters (e.g. ZI-acetate) of A pregnene-l1a,17a,21-triol-3,20-dione (also known as epi F), as well as the 4,5-dihydro derivatives of each of these. Tzhese bromo derivatives are then dehydrobrominated by heating with a base, such as collidine with or without a lithium halide salt, or with a lithium halide salt in a lower iatty acid amide (e.g. dimethylfor-mamide) to form a mixture of the corresponding A and A -pregnadiene derivatives which are separated chromatographically. These A -11a-hydroxy derivatives are then subjected to the conversion disclosed for lla-hydroxy derivatives in US. Patent No. 2,852,511 to obtain the compounds of this invention. Thus, the llwhydroxy 4,6-pregnadienes are reacted with a sulfonyl halide, such as tosyl chloride, to form the corresponding lla-sulfonyloxy {c.g. 110ctosyloxy) derivatives, which in turn are heated, for example, with sodium acetate and acetic acid, to form the corresponding A -pregnatriene derivatives. These derivatives are then hydroxybrominated, with say N- bromoacetamide, to form the corresponding 9a-bromo llfi-hydroxy derivatives, which in turn can be oxidized with chromic oxide to form the corresponding 9 x -bromoll-keto derivatives, or can be converted with potassium acetate to the corresponding 95,11fi-oxido derivatives. These 95,1lfl-oxido derivatives can then be reacted with a hydrogen halide, such as hydrofluoric acid, hydrochloric acid or hydroiodic acid to form the corresponding halo-lLB-hydroxy derivatives, and these derivatives can then be oxidized with chromic oxide to the corresponding 9u-halo-1l-keto derivatives.

The preparation of 11u-hydroxy-u flpregnadienes utiliza'ble in the foregoing process of this invention is illus- 13 trated by the following example, wherein M -pregnadiene-llot,17a,21-triol-3,20-dione 2l-ra'cetate is prepared from A pregnene-l 1a,17a,2l-tIlOl-3,2Q'-di01l6.

EXAMPLE 7 A solution of 8.0 g. of u apregnene-lla,17u,2l-triol- 3,20-dione in 500 ml. of 95% alcohol is shaken in an atmosphere of hydrogen at room temperature and ordinary pressure in the presence of l g. of a Pd on charcoal catalyst. After the absorption of 630 ml. of hydrogen, the reduction comes to a standstill. The catalyst is filtered off and the solvent removed completely in high vacuum. The mixture of pregnane-l1a,17u,21-triol-3,20- dione and the corresponding allopregnane is separated chromatographically as described in U.S. Patent No. 2,659,744.

720 mg. of the allopregnane-l1a,17a,21-triol-3,20-dione thus recovered is acetylated in the 21-position only by dissolving it in 5 ml. of dry pyridine and adding to the solution 210 mg. of acetic 'anhydride. After 18 hours at room temperature, the mixture is diluted with Water and chloroform. The chloroform extract is washed with Water, 1 N hydrohcloric acid, sodium bicarbonate and again with water, dried over sodium sulfate and the solvent removed in vacuo.

The resulting allopregnane-lla,l7a,2l-triol-3,20-dione 2l-acetate is dissolved in 40 ml. of glacial acetic acid and to the solution is added slowly with stirring 7.6 ml. of a solution of bromine in ace-tic acid (80 mg. Br /ml.). When all the bromine has been adsorbed, 370 mg. of solid potassium acetate is added and the mixture concentrated to a small volume in vacuo. Water and chloroform is added and after separation of the layers, the chloroform extract is washed with sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue, consisting essentially of 2,4-dibromoallopregnane-l la, 17 04,21-t1l0l- 3,20-dione 21-acetate, is dissolved in ml. of collidine and the resulting solution boiled under reflux for 4 hour in an atmosphere of nitrogen. The mixture is then treated th chloroform and sufiicient 1 N hydrochloric acid to remove all the collidine from the chloroform solution and the latter washed with sodium bicarbonate solution and water. Evaporation of the solvent in vacuo leaves a residue, from which the A -pregnadiene-1la,l7a,21- triol-3,20-di0ne 2l-acetate is separated by chromatography on 12 g. of sulfuric acidwashed alumina. For this purpose, the residue is dissolved in 4 ml. of chloroform and 12 ml. of benzene, poured on the column and the latter eluted with a solvent mixture containing 1 volume of chloroform and three volumes of benzene, which removes some amorphous material. When the eluate is changed to chloroform A -pregnadiene-11a,l7u,2l-triol- 3,20-dione Zl-aceta-te is eluted, followed by d pregnadiene-l111,17a,21-triol-3;20-dione 21-acetate.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A steroid of the pregnadiene series, unsaturated in the 4,5 and 6,7 positions and having a 9ix-halo group, 0x0 groups in the 3- and -positions, and a substituent selected from the class consisting of B-hydroxy and keto in the ll-position.

2. A steroid of the formula wherein individually R" is hydrogen, R is fl-hydroxy and together R" and R' is keto; X is an u-halogen group; Z is selected from the group consisting of hydrogen and a-hydroxy; and Y is selected from the group consisting of hydrogen, hydroxy and the acyloxy of a hydrocarbon carboxylic acid of less than ten carbon atoms.

3. A compound selected from the classconsisting of 9a-halo-A -pregnadiene-115,17a,21-ttriol-3,20-dione and 21- esters thereof with hydrocarbon carboxylic acids of less than ten carbon atoms.

4. A compound selected from the class consisting of 9a-haloA -pregnadiene-17a,2'l-dio1-3,11,20 trione and 21-esters thereof with hydrocarbon carboxylic acids of less than ten carbon atoms.

5. 9a-fluoro-A -3J1,20-triketo 1704,21 dihydroxy pregnadiene 2l-ace-"tate CHrO O C CH3 I 0 ro 6. 9afiuor0-A -3,2O-diketo 1118,17ot-21 trihydroxypregnadiene 21-acetate CHtOOCCHa I CHzY wherein Z is selected from the group consisting of hydrogen and ot-hydroxy; and Y is selected from the group consisting of hydrogen, hydroxy and the acyl oxy of a hydrocarbon carboxylic acid of less than ten carbon atoms.

13. A compound selected from the class consisting of 9,8,11,8-'OXldO-A -pI6gI1fldlCI1-1706,21 d'iol 3,20-dione and 2l-esters thereof with hydrocarbon carboxylic acids of less than ten carbon atoms.

14. 95,11fi-oxido-A -pregnadiene-17w-o1 3,20 dione.

15. 9B,l1B-oxido-A -preg-nadiene-21-ol-3,20-dione.

16. A process for preparing a steroid of the pregnadiene series unsaturated in the 4,5 and 6,7 positions, and having a 9a-haio group and a substituent selected from the class consisting of li-hydroxyand keto in the lit-position, which comprises reacting the corresponding saturated allopregnane derivative with two moles of bromine per mole of steroid, and dehydrobrorninating the compound thus formed.

References Cited in the file of this patent UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 105 832 October I v 1963 Josef Fried It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3 lines 62 to 72 the formula should appear as shown below instead of as: in the patent:

below the sec ond formula u for "VII R *--R"" O) X CI" read VII R +R Ol X F same columns 5 and 6, below the fifth formula E for "XVIII R :H g R g- OH; X C-l" read XVIII R H; R"" B--OH; X CI 12th day of May 1964p columns 5 and 6 Signed and sealed this (SEAL) Attest: ERNEST We SWIDER EDWARD Jo BRENNER Attesting Officer Commissioner of Patents 

12. A STEROID OF THE FORMULA 